Role of CLIC5 in Podocyte Injury and Remodeling

CLIC5 在足细胞损伤和重塑中的作用

基本信息

批准号：
8898791
负责人：
Cynthia Tsui
金额：
$ 7.75万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-28 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898791
关键词：
Actins Adherence Adhesions Adriamycin PFS Adult Animal Model Apical Architecture Basement membrane Biochemical Biological Biological Markers Biotinylation Cell Death Cell Fractionation Cell Line Cell membrane Cell surface Cells Cessation of life Chloride Channels Chloride Ion Chlorides Chronic Kidney Failure Clinical Complex Data Disease Disease Progression Family Focal Segmental Glomerulosclerosis Foot Process Foundations Functional disorder Genetic Genetic Polymorphism Goals Hair Cells Health Human Immunofluorescence Microscopy In Vitro Injury Integral Membrane Protein Intervention Kidney Diseases Laboratories Length Life Literature Living Donors Maintenance Measures Mediating Mediator of activation protein Membrane Proteins Membranous Glomerulonephritis Messenger RNA Methods Modeling Molecular Morphogenesis Mus NPHS2 protein Natural regeneration Pathogenesis Patients Periodic acid Schiff stain method Prevention Process Proteins Proteinuria Public Health Recovery Renal glomerular disease Role Sampling Sialic Acids Signal Pathway Signal Transduction Staging Stereocilium Structure Testing Therapeutic Urine Variant apical membrane base cell injury cellular imaging density design experience ezrin glomerular basement membrane glomerular filtration in vivo light microscopy novel podocalyxin podocyte protein expression repaired research study response response to injury sialylation tool trafficking

项目摘要

DESCRIPTION (provided by applicant): In many glomerular diseases, proteinuria and disease progression are associated with podocyte loss by death or detachment. Understanding the mechanisms by which the podocyte maintains attachment and recovers by remodeling its large and foot processes after injury is critical for the identification of potential therapeutic targetsof glomerular diseases. Podocalyxin is an apical membrane protein that is required for the formation of podocyte large and foot processes. A decrease in the sialylation and expression of podocalyxin are associated with glomerular diseases. Chloride intracellular channel 5 (CLIC5) is an apical membrane protein that associates with podocalyxin and ezrin, and is an important intermediate adapter between the cell membrane and the cytoskeletal network. We have recently discovered that CLIC5-deficient podocytes display foot process effacement and a decrease in podocalyxin protein expression. CLIC5 protein expression is decreased in Minimal Change Disease compared with normal human living donors. Our long term goal is to identify and understand the proteins and signaling pathways necessary for podocyte survival and remodeling in response to glomerular injury. The aims of this proposal are twofold. First, we will determine the extent to which CLIC5 controls the proper trafficking and stability of podocalyxin in podocyte processes. Second, we will identify the role of CLIC5 in maintaining podocyte adhesion in response to glomerular injury in vivo. This project is significant because we will demonstrate a novel mechanism that is critical for podocyte recovery from injury. A combination of biochemical and cell biological approaches will be employed in cultured Clic5-deficient podocytes and Clic5-deficient mice. We expect to identify CLIC5 as a protein critical for podocytes to recover by maintaining their adherence to the glomerular matrix and to remodel their foot processes to reestablish the glomerular filtration barrier. The results of these experiments may aid in establishing a foundation for the rational design of effective clinical interventions for glomerular diseases.

描述（由申请人提供）：在许多肾小球疾病中，蛋白尿和疾病进展与死亡或脱离导致的足细胞损失相关。了解足细胞在损伤后通过重塑其大突和足突来维持附着和恢复的机制对于识别肾小球疾病的潜在治疗靶点至关重要。足萼蛋白是一种顶膜蛋白，是形成足细胞大和足突所必需的。足细胞萼蛋白唾液酸化和表达的减少与肾小球疾病相关。氯离子胞内通道 5 (CLIC5) 是一种顶膜蛋白，与足萼蛋白和埃兹蛋白结合，是细胞膜和细胞骨架网络之间的重要中间接头。我们最近发现 CLIC5 缺陷的足细胞表现出足突消失和足萼蛋白表达减少。与正常人类活体供体相比，微小病变病中的 CLIC5 蛋白表达降低。我们的长期目标是识别和了解足细胞存活和重塑以响应肾小球损伤所需的蛋白质和信号通路。该提案的目的是双重的。首先，我们将确定 CLIC5 在多大程度上控制足细胞过程中足萼蛋白的适当运输和稳定性。其次，我们将确定 CLIC5 在响应体内肾小球损伤维持足细胞粘附中的作用。这个项目意义重大，因为我们将展示一种对于足细胞从损伤中恢复至关重要的新机制。生物化学和细胞生物学方法的结合将用于培养 Clic5 缺陷足细胞和 Clic5 缺陷小鼠。我们期望将 CLIC5 确定为对足细胞恢复至关重要的蛋白质，通过维持足细胞对肾小球基质的粘附并重塑其足突以重建肾小球滤过屏障。这些实验的结果可能有助于为肾小球疾病有效临床干预措施的合理设计奠定基础。